Fornasieri A, Li M, Armelloni S, de Septis C P, Schiaffino E, Sinico R A, Schmid C, D'Amico G
Division of Nephrology and Pathology, San Carlo Borromeo Hospital, Milano, Italy.
Lab Invest. 1993 Nov;69(5):531-40.
Human cryoglobulinemia is sometimes associated with glomerulonephritis (GN) due to deposition of cryoglobulins (cryos). To see whether human cryos can induce GN in mice and to study time-related changes of glomerular lesions and possible factors of cryos' nephritogenicity, we developed an experimental passive model of cryoglobulinemic GN.
Two cryos IgMk-IgG from 2 patients with active GN (OLD and SOR), 2 cryos IgMk-IgG (TAC and GRO) and 1 IgM lambda (CHI) from 3 patients without GN were purified, solubilized at 37 degrees C and injected intravenously into BALB/c mice, 4 mg, twice a day. To study the possible factors of cryo nephritogenicity, we analyzed: (a) the presence, amount, and size of complexed IgMk-IgG at 37 degrees C by fast flow liquid chromatography; (b) the Cc1 or Lc1 subclass of rheumatoid factors; (c) the isoelectric points of the IgMks; (d) The proportion of IgG subclasses in cryos.
On day 1 from the beginning of intravenous injections, cryos OLD had induced mesangial deposits of human IgM, human IgG, mouse C3 and mesangial hypercellularity. On day 2, phagocytizing cells were found along with massive endoluminal and subendothelial deposits of IgM, IgG, and C3. On day 6, perivascular infiltrates of mononuclear cells were also seen. Cryos SOR induced a similar but milder form of GN. After administration of purified OLD IgMk, OLD IgG, GRO IgMk or GRO IgG, only OLD IgMk was deposited in the mesangium. Analysis of all the cryos revealed that: the amount of complexed IgMk-IgG at 37 degrees C was always less than 1% of cryos; Cc1 and Lc1 idiotypes were not related to the nephritogenicity of cryos, the isoelectric points of IgMks were 4.5 to 5.5 and IgG1 was the prevalent subclass.
Data demonstrate that human cryos from patients with GN can induce GN in mice that resembles the corresponding human pathology. The affinity of IgMk for glomeruli and the unexpectedly small amounts of IgMk-IgG complexes at 37 degrees C suggest that there is a role of in situ binding in nephritogenicity which is independent of the isoelectric point, rheumatoid factor idiotype, or IgG subclass.
人类冷球蛋白血症有时与肾小球肾炎（GN）相关，原因是冷球蛋白（cryos）沉积。为了观察人类冷球蛋白是否能在小鼠中诱发GN，并研究肾小球病变的时间相关变化以及冷球蛋白致肾炎性的可能因素，我们建立了冷球蛋白血症性GN的实验性被动模型。
从2例活动性GN患者（OLD和SOR）中纯化出两种冷球蛋白IgMκ-IgG，从3例无GN患者中纯化出2种冷球蛋白IgMκ-IgG（TAC和GRO）以及1种IgMλ（CHI），在37℃溶解后静脉注射到BALB/c小鼠体内，剂量为4mg，每日两次。为了研究冷球蛋白致肾炎性的可能因素，我们分析了：（a）通过快速流动液相色谱法分析37℃时复合IgMκ-IgG的存在、数量和大小；（b）类风湿因子的Cc1或Lc1亚型；（c）IgMκ的等电点；（d）冷球蛋白中IgG亚类的比例。
从静脉注射开始第1天，冷球蛋白OLD诱导了人IgM、人IgG、小鼠C3的系膜沉积以及系膜细胞增多。第2天，发现吞噬细胞以及IgM、IgG和C3的大量管腔内和内皮下沉积。第6天，还可见血管周围单核细胞浸润。冷球蛋白SOR诱导了类似但较轻的GN形式。给予纯化的OLD IgMκ、OLD IgG、GRO IgMκ或GRO IgG后，只有OLD IgMκ沉积在系膜中。对所有冷球蛋白的分析表明：37℃时复合IgMκ-IgG的量始终小于冷球蛋白的1%；Cc1和Lc1独特型与冷球蛋白的致肾炎性无关，IgMκ的等电点为4.5至5.5，IgG1是主要亚类。
数据表明，来自GN患者的人类冷球蛋白可在小鼠中诱发类似于相应人类病理的GN。IgMκ对肾小球的亲和力以及37℃时意外少量的IgMκ-IgG复合物表明，原位结合在致肾炎性中起作用，这与等电点、类风湿因子独特型或IgG亚类无关。
